Education

Research: Neurotoxicology

The primary focus of our research is on selective vulnerability of the nervous system to neurotoxic chemicals. We are using two compounds, cyanide and trimethyltin, as model neurotoxicants that produce selective lesions in the brain. Following subacute exposure to cyanide necrotic lesions develop within the striatum and basal ganglia, brain areas that are involved in regulation of movement. These animals developed a Parkinson-like syndrome similar to that reported in human toxicity following cyanide exposure. On the other hand, neurons in the cortical brain areas undergo an apoptotic cell death in which gene activation appears to initiate cell death. We have characterized and documented that cyanide produces selective brain lesions by necrotic or apoptotic processes, and we have developed a tissue culture model for studying the underlying mechanisms of the cell death. Initially, cyanide activates the NMDA glutamate receptor system leading to activation of a series of intraneuronal cascades resulting in excessive production of reactive oxygen species and nitric oxide. These products then produce oxidative stress and active redox sensitive transcription factors and the intracellular apoptotic cascade. In the case of trimethyltin, low doses produce selective loss of the dentate granule cells of the hippocampus, a brain area involved in short term memory. This cell loss involves apoptotic death linked to oxidative stress. Studies are directed at determining the sequence of intracellular cascades selectively activated by trimethyltin and the relationship to this type of neuronal death. We are presently addressing why select brain areas are vulnerable to this injury and how the oxidative stress leads to neuronal apoptosis. By understanding these toxic responses in detail, insight to the causes of neurodegenerative diseases will be gained and the potential etiologic role of environmental exposure to chemicals in neurodegeneration can be determined.